tbuckley/cabot-search huggingface dataset:
Type of endocrine therapy and DFS in patients with early HER2+/HR+ BC: Analysis from the phase III randomized ShortHER trial.
Authors: Maria Vittoria Dieci, Giancarlo Bisagni, Alba Ariela Brandes, Antonio Frassoldati, Roberto Vicini, Sara Balduzzi, Roberto D'Amico, Pier Franco Conte, Valentina Guarneri
Journal: Journal of Clinical Oncology (2022)

547 Background: Optimal adjuvant endocrine therapy for HER2+/HR+ patients treated with chemotherapy and trastuzumab is still unclear. We evaluated the impact of the type of endocrine therapy on DFS in patients with HER2+/HR+ breast cancer enrolled in the phase III ShortHER trial. Methods: The Short-HER study randomized 1254 patients with HER2+ early breast cancer to receive 9 weeks vs 1 year of adjuvant trastuzumab combined with anthracycline-taxane chemotherapy. The type of adjuvant endocrine was collected every 6 months during the first 5 years of follow-up and was classified as: aromatase inhibitor (AI), tamoxifen and aromatase inhibitor (TAM-AI, in case of both drugs were administered for at least 1 year each), or tamoxifen (TAM). For premenopausal patients, the use of GnRH analogue was also collected. DFS was calculated from randomization to disease recurrence (locoregional or metastatic), second primary invasive cancer, or death. Results: 853 patients with HR+ BC (ER and/or PgR &gt;10%) were included: 60% postmenopausal, 40% premenopausal. The pattern of endocrine therapy was: 55% AI, 22% TAM, 15% TAM-AI (8% missing data). Among premenopausal patients, 51% received GnRH. At a median follow up of 8.7 years (IQR 7.6-9.0), patients who received AI had a significantly better DFS as compared to patients who received TAM or TAM-AI: 7-yr DFS 87.3% vs 81.7%, log-rank P=0.017 (HR 1.46, 95%CI 1.05-2.03). In multivariate analysis including menopausal status, stage, and treatment arm, the type of endocrine therapy maintained a significant association with DFS (Table). In the subgroup of premenopausal patients, the use of GnRH was associated with numerically improved DFS: 86.6% vs 81.6%, log-rank P=0.168 (HR=0.70, 95%CI 0.43-1.16). Conclusions: In this post-hoc analysis of the ShortHER trial, adjuvant treatment with aromatase inhibitor was independently associated with improved DFS. Subgroup analysis in premenopausal patients suggests potential benefit with ovarian suppression. Clinical trial information: NCT00629278. [Table: see text]
Efficacy and safety of bosutinib in later-line patients (pts) with chronic myeloid leukemia (CML): A sub-analysis from the phase 4 BYOND trial.
Authors: Carlo Gambacorti-Passerini, Tim H. Brümmendorf, Thomas Ernst, Eric Leip, Simon Purcell, Andrea Viqueira, Francis J. Giles, Gianantonio Rosti, Andreas Hochhaus
Journal: Journal of Clinical Oncology (2022)

e19055 Background: Bosutinib (BOS) is approved for pts with Philadelphia chromosome-positive CML resistant/intolerant to prior therapy and newly diagnosed pts in chronic phase. Methods: The BYOND trial (NCT02228382) evaluated the efficacy and safety of BOS in 163 pts with CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs; Gambacorti-Passerini et al, Blood, 2021). We report a sub-analysis of 48 pts treated with 2 (3L) and 3 (4L) prior TKIs, categorized by resistance/intolerance to the last received TKI. This sub-analysis is based on the final Nov 23, 2020 database lock. Results: There were 18 and 30 pts resistant or intolerant to the last TKI who entered the study without complete cytogenetic response (CCyR) or major molecular response (MMR), respectively. Median (range) treatment duration was 10.6 mo (1.6–48.5) vs 28.3 mo (0.2–48.6) and median (range) dose intensity was 447.1 mg/d (131.3–520.4) vs 288.8 mg/d (79.7–500.0) for resistant vs intolerant pts. Prior TKIs included imatinib (88.9% vs 100.0%), dasatinib (88.9% vs 83.3%), and nilotinib (66.7% vs 63.3%) for resistant vs intolerant pts. Overall, 61.1% vs 66.7% of resistant vs intolerant pts discontinued BOS, mostly commonly due to adverse events (AEs) in 27.8% vs 16.7% pts; 16.7% vs 6.7% discontinued BOS due to insufficient clinical response. Rates of CCyR/MMR are shown in the table. Among responders (resistant vs intolerant pts), median (range) time to CCyR was 5.1 mo (2.8–8.8) vs 3.0 mo (2.7–6.1); median (range) time to MMR was 5.8 mo (2.8–9.4) vs 3.2 mo (2.8–9.3). In resistant vs intolerant pts, any grade treatment-emergent AEs (TEAEs) were reported by 100.0% vs 96.7% pts; grade 3/4 TEAEs were reported by 72.2% vs 83.3% pts. Grade 3/4 TEAEs &gt; 10% in resistant pts were thrombocytopenia (22.2%) and neutropenia (11.1%), and in intolerant pts were increased alanine aminotransferase (26.7%), diarrhea (23.3%), pleural effusion (13.3%), and rash (13.3%). Conclusions: This sub-analysis of resistant/intolerant pts without baseline CCyR or MMR shows BOS was active in heavily pretreated pts with resistance/intolerance to the last TKI. Despite a difference between resistant/intolerant pts, efficacy outcomes, though lower than the overall BYOND population, are encouraging, and safety was generally consistent with previous reports. Clinical trial information: NCT02228382. [Table: see text]
LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)
Authors: Anna Vinitsky, Jason Chiang, Asim K Bag, Olivia Campagne, Clinton F Stewart, Paige Dunphy, Barry Shulkin, Qian Li, Tong Lin, Mary Ellen Hoehn, Jason N Johnson, Jeffrey A Towbin, Raja Khan, Ruth G Tatevossian, Gregory T Armstrong, Brian Potter, Heather Conklin, Todd Shearer, Susan Scott, Giles W Robinson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: MEK inhibitor trials in pediatric low-grade glioma (pLGG) have yielded promising results, but there remains room for improvement since objective responses are rarely complete and disease recurrence after completion of therapy is common. Mirdametinib (PD-0325901) is a highly selective MEK1/MEK2 inhibitor that, in preclinical studies, has been reported to have superior blood-brain-barrier penetration compared to other MEK inhibitors. As such, we recently launched the SJ901 clinical trial (NCT04923126) to determine the safety, recommended phase 2 dose, pharmacokinetics, and preliminary efficacy of mirdametinib in patients with pLGG when administered continuously. Here, we present preliminary phase 1 data. METHODS: SJ901 is a multi-arm phase I/II trial of mirdametinib in patients &amp;gt;2 and &amp;lt;25 years with LGG. Phase I requires participants to have no prior exposure to MEK inhibitors and recurrent/progressive disease with biopsy-proven evidence of MAPK pathway activation. Three escalating dose levels (2 mg/m2/dose BID, 2.5mg/m2/dose BID and 3mg/m2/dose BID) are planned using a rolling 6 design. RESULTS: Accrual began in June 2021. As of Jan 13, 2022, eleven patients enrolled: 5 on dose level 1 (DL1) and 6 on dose level 2 (DL2). Median age is 10 (3-21) years. Ten patients have somatic gene rearrangements (7 BRAF, 1 MYB, 1 RAF1, 1 FGFR1) and one has an NF1 germline mutation. Four have metastatic disease. No dose-limiting toxicities occurred for DL1 (whereas data are pending for DL2) and only grade 1/2 treatment-related adverse events have been observed. No MEK-related retinopathy or cardiopathy has been observed. Four of the six patients with at least one follow-up disease evaluation have a minor response (&amp;gt;25%-&amp;lt;50% decrease). Median time on therapy is 6.6 (2.2-7) months. No disease progressions have occurred. CONCLUSION: Thus far, mirdametinib is well-tolerated and clinically promising when dosed continuously in patients with recurrent/progressive pLGG. More information will be forthcoming.
The emergence of a multidrug resistant Salmonella Muenchen in Israel is associated with horizontal acquisition of the epidemic pESI plasmid
Authors: Emiliano Cohen, Or Kriger, Sharon Amit, Maya Davidovich, Galia Rahav, Ohad Gal-Mor
Journal: Clinical Microbiology and Infection (2022)

Horizontal acquisition of mobile genetic elements is a powerful evolutionary driving force that can profoundly affect pathogens epidemiology and their interactions with the environment and host. In the last decade, the role of the epidemic megaplasmid, pESI was demonstrated in the global emergence of multi-drug resistant (MDR) Salmonella enterica serovar Infantis strains, but it was unknown if this was a one-time phenomenon, or that pESI can drive the emergence of other pathogens.Epidemiological, molecular, whole genome sequencing, de-novo assembly, bioinformatics and genetic approaches were used to analyze the emergence of a pESI-positive Salmonella enterica serovar Muenchen strain in Israel.Since 2018, we report the emergence and high prevalence of S. Muenchen in Israel, which consisted at 2020, 40% (1055/2671) of all clinical Salmonella isolates. We show that the emergence of S. Muenchen is dominated by a clonal MDR strain, report its complete assembled genome sequence, and demonstrate that in contrast to preemergent strains, it harbors the epidemic megaplasmid, pESI, which can be self-mobilized into E. coli and other Salmonella serovars. Additionally, we identified bioinformatically highly similar genomes of clinical isolates that were recently collected in South Africa, UK and USA.This is a second documented case of a pathogen emergence associated with pESI acquisition. Considering the genetic cargo of pESI that enhances resistance, stress tolerance and virulence, and its ability to conjugate into prevalent Salmonella serovars, we provide further support that pESI facilities the emergence and spreading of new Salmonella strains.
Micro-ultrasound-guided biopsy for prostate cancer reduces underestimation of index lesion extension at final pathology compared to mri/ultrasound prostate fusion biopsy: Impact on ablation therapy templates
Authors: R.C. Castilho Borges, C.K.O. Kauffman Ortega, R.R.T.B. Rocha Tourinho Barbosa, F.P. Pugliesi, L.H. Haiquel, L.C. Candela, C.L. Lanz, L.R.S. Rodriguez Sanchez, O.R.C. Rojas Claros, R.S. Sanchez-Salas, P.M. Macek, X. Cathelineau
Journal: European Urology (2022)
Predicting response to naratuximab emtansine, an anti-CD37 antibody-drug conjugate (ADC), in combination with rituximab in diffuse large B-cell lymphoma (DLBCL), by analyzing the spatial arrangement of CD37 and CD20 positive cells using deep learning.
Authors: Anna Pokorska-Bocci, Sandrine Micallef, Mariola Dymkowska, Yuval Gabay, Roman Gluskin, Avi Laniado, Efrat Dicker Sagy, Amit Bart, Tomer Dicker, Ifat Rotbein, Albert Achtenberg, Ori Zelichov
Journal: Journal of Clinical Oncology (2022)

e19565 Background: DLBCL is the most common type of Non-Hodgkin’s lymphoma, accounting for 30-40% of cases. Despite improvements in response and survival with standard of care treatment, up to 40% of patients have relapsed and/or refractory (R/R) disease. A phase 2 study (NCT02564744) evaluated the efficacy of naratuximab emtansine, an anti-CD37 ADC, in combination with rituximab, in 80 patients with R/R DLBCL. We performed an exploratory analysis of the study to find pathology-based biomarkers predictive of response. Deep learning (DL) models were used to extract spatial features from digitized slides stained with CD37 and CD20 and their predictive role was evaluated. Methods: A cohort of 47 DLBCL patients from the study were selected based on availability of CD20/CD37 IHC staining and were used for analysis. Patient characteristics of the analyzed cohort were similar to those of the full study cohort. Overall response rate (ORR) of the analyzed cohort was 44.7%, similar to the ORR of the full study cohort. For each patient, whole slide images (WSI) of two slides from a pre-treatment biopsy, one stained for CD20 and one for CD37, were analyzed. DL models were used to classify cells as positive or negative to the two markers and CD20/CD37 co-expression was analyzed. Over 140 spatial features were pre-defined based on drug mechanism of action and biological hypotheses, and were calculated for each patient using cell classifications. A repeated 5-fold cross-validation analysis was performed to identify features predictive of objective response. Results: Two spatial features related to the proximity of CD37 and CD20 positive cells, demonstrated a significant correlation with clinical outcome. Each feature identified patients in the cohort as having either a positive or a negative response. Feature performance was estimated using 2000 repetitions of 5-fold cross-validation. One feature classified on average 21% of patients as responders. Patients positive for this feature had an average ORR of 78% (95% CI 64%-82%), an increase of 34% in ORR relative to the original cohort (p &lt; 0.05). The second feature classified on average 35% of patients as positive. Patients positive for this feature had an average ORR of 67% (95% CI 62%-71%), an increase of 23% in ORR relative to the original cohort (p &lt; 0.05). Conclusions: DL analysis of the co-expression and spatial arrangement of CD37 and CD20 in pre-treatment biopsies of DLBCL patients could potentially be used as a predictive biomarker for a response to a combination treatment of anti-CD37 and anti-CD20 drugs in DLBCL, and may improve patient stratification for further clinical trials.
Serological markers associated with response and adverse events in patients of esophageal squamous carcinoma with toripalimab combined with nab-paclitaxel and S-1 as neoadjuvant therapy.
Authors: Guoqing Zhang, Jing Yuan, Qing Xu, Jing Zhang, Minglu Liu, Zhigang Song, Liang Liang Wu, Bo Yang, Yi Hu, Shunchang Jiao, Haitao Luo, Xiaoli Cui, Chaohu Pan
Journal: Journal of Clinical Oncology (2022)

e16017 Background: Immune checkpoint inhibitor (ICI) combined with chemotherapy as a neoadjuvant therapy has been applied to the treatment of patients with esophageal squamous carcinoma (ESCC), however, there were a limited number of predictive biomarkers for response and adverse events. Methods: 60 patients diagnosed with ESCC and considered propable for surgical treatment were enrolled from October 2019 to September 2020 in the first medical center of Chinese PLA General Hospital and received Toripalimab combined with nab-Paclitaxel and S-1 as neoadjuvant therapy. Serum samples were collected at baseline and performed with 92 proteins using proximity extension assay technology. Results: In total, 50 patients were examined, and 3 patients did not pass quality control. Patients with IFN-Y-L, LAMP3-L and Gal.1-H at baseline were associated with longer overall survival. Furthermore, 21 proteins were found to be significantly lower in patients with severe side effects than in patients without serious adverse events. Conclusions: Our study found that serum levels of several proteins were associated with clinical benefit and severe side effects, and these proteins may be useful biomarkers for predicting response and severe side effects in ESCC treated with ICI and chemotherapy.
DIPG-53. Long-term survival from a Phase 1 dose-escalation trial using convection-enhanced delivery (CED) of radioimmunotherapeutic124I-omburtamab for treatment of diffuse intrinsic pontine glioma (DIPG).
Authors: Mark M Souweidane, Kim Kramer, Neeta Pandit-Tasker, Sofia Haque, Pat Zanzonico, Jorge Carrasquillo, Serge K Lyashchenko, Sunitha B Thakur, Yasmin Khakoo, Ira J Dunkel, Maria Donzelli, Jason S Lewis, Nai-Kong V Cheung, Steve M Larson, Anne S Reiner, Katherine S Panageas, Nicole Manino, John Rømer Nielsen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Median survival from DIPG is less than one year. In a phase 1 dose escalation study (clinicaltrials.gov NCT01502917) 124I-omburtamab targeting B7-H3 was administered intratumorally using CED. METHODS: CED was performed between 4-14 weeks post radiation therapy. Using a 3 + 3 design, 124I-omburtamab was escalated from 0.25-10.0 mCi and infusion volumes (Vi) from 250-10,000 µl with serial 124I PET/CT performed up to ~1 week post-administration. Toxicities were assessed for 30 days. Dose escalation safety was evaluated. Survival was calculated using Kaplan-Meier statistics. RESULTS: 46 children were treated and evaluable for toxicity and survival;4 patients received partial doses and were evaluable for toxicity only. Three patients experienced dose limiting toxicities. Eleven patients had transient treatment related grade 3 toxicities with no grade 4 or 5 toxicities. Grade 3 nervous system toxicities included: muscular weakness(n=8), dysarthria(n=4), ataxia(n=3), dysphagia(n=3), and gait disturbance(n=1). Lesion absorbed doses ranged from 1,000-1,500cGy/mCi, with lesion-to-whole body radiation absorbed-dose ratios of ~900. A dose of 8mCi and infusion volume of 8,000 µl is safe and may provide a distribution volume up to 20cm3. Median survival was 15.3 months (n =46, 95% CI 12.7, 17.3). Survival rate estimates (95% CI) at 1, 2, 3 and 5 years were 0.67 (0.55;0.82); 0.18 (0.09;0.35); 0.10 (0.04;0.26); and 0.05 (0.01;0.20). Four patients survived &amp;gt;3 years; two remain alive (61+ and 106+ months);two have died (44 and 53 month) with distant CNS disease and one with extra-CNS metastasis. CONCLUSION: Administration of escalating doses and volumes of 124I-omburtamab via CED was a viable option for this patient subgroup. The median overall survival was increased 3-4 months compared to historical controls. Anecdotal long-term survival if validated with a planned phase 2 trial would support the concept of whole neuroaxis treatment in combination with CED in a subset of DIPG patients.
Assessment of systematic and combined MRI-targeted biopsy for prostate cancer diagnosis during 10 years of practice at a single institution
Authors: L. Lenfant, R. Renard-Penna, Y. De Rycke, M. Roupret, A. Baugerie, E. Comperat, E. Chartier-Kastler, P-C. Mozer
Journal: European Urology (2022)
Clinical implications of next-generation sequencing on pediatric solid tumors.
Authors: Wei Guo, Lu Xie, Jie Xu, Lijuan Chen, Liwei Wang, Aodi Wang, Mingmin Wang, Xiaowei Dong, Lei Mei, Hui Chen, Shaohua Yuan, Kai Wang
Journal: Journal of Clinical Oncology (2022)

e22012 Background: To assess the impact of next-generation sequencing (NGS) on Chinese pediatric cancer, we reported the first study of largest cohort in Chinese children with genomic landscape and highlighted the potential application with respect to molecular diagnosis and predictive biomarkers etc. Methods: A retrospective analysis was conducted on patients aged &lt; 19 years diagnosed with solid tumors sequenced by targeted NGS panel. Somatic variants were analyzed following CAP/CLIA-certificated workflows, including Single Nucleotide Variant (SNV), Copy Number Variation (CNV), large insertion and deletions (Lindel) and gene rearrangements. Results: A total of 356 patients enrolled with three major cancer types including osteosarcoma (OS) (n = 78), rhabdomyosarcoma (RMS) (n = 51), Ewing sarcoma (EWS) (n = 13). Hepatocellular carcinoma (n = 9), medulloblastomas (n = 7) and colorectal adenocarcinoma (n = 5) were also included. 3487 somatic alterations were identified, TP53 (16%), EWSR1 (8.7%), CDKN2A (7.8%), BCOR (7%) and RB1 (5.6%) rank the top five reported. TP53 (21% % vs 7.9%), RB1 (10% vs 5.3%) mutations showed higher frequency in OS and BCOR (14% vs 17.6%) showed lower frequency in RMS compared to published paper (Gröbner et al 2018). We found PIK3CA mutations presented in RMS with 11.7% frequency, twice than reported (5.8%), mostly occurring at the known oncogenic codon E545. The obscure boundary of soft tissue tumor and bone tumor perplexed the pathologic diagnosis, NGS provide an important auxiliary examination. In 140 soft tissue tumor and bone tumor patients, 14.2% patients were further diagnosed with different subtype, 4.2% patients with unknown subtype were diagnosed with a specified subtype by supportive genetic alterations. Moreover, 41.5% (138/356) patients received treatment recommended . Twelve NTRK-fusions were detected and the patients were recommended therapy method upon Larotrectinib, recruitment in matched clinical trial is still on-going. Conclusions: We investigated the different genetic profiling of Chinese pediatric solid cancer and found the clinical value of NGS in pathological diagnosis and biomarker discovery.
Laparoscopic colposacropexy: Comparative anatomy of the ovine and female pelvis
Authors: V.N. Viegas Madrid, M. Costal, S. Enciso Sanz, B. Fernandez Tomé, I. Diaz-Güemes, F. Sánchez Margallo, D. Carracedo, L. López-Fando Lavalle
Journal: European Urology (2022)
Cyclin-dependent kinase 6 body methylation and association with prognosis of patients with acute myeloid leukemia.
Authors: Lei Zhang, Rui Ma, Qingxiang Yu, Lihua Sun
Journal: Journal of Clinical Oncology (2022)

e19000 Background: Cyclin-dependent kinase 6 (CDK6) plays critical roles in leukemogenesis and leukemia stem cells activation, and its inhibition has emerged as a novel therapeutic strategy in acute myeloid leukemia (AML) management. However, association between CDK6 methylation and prognosis in patients with AML remains unclear. Methods: Methylation profile, somatic alterations, and CDK6 gene expression data of 200 clinically annotated patients with de novo AML were retrieved from the TCGA Pan-Cancer Atlas project deposited in the UCSC Xena database. Specifically, methylation levels of all 64 CpGs across CDK6 were extracted, and then methylation abundances of promoter and gene body regions were calculated as average levels of CpGs located in the respective regions. Patients were categorized into two subgroups (hypo- and hyper-methylated) as per the median methylation level for either region or single CpG site. Log-rank tests were conducted to compare overall survival (OS) of patients stratified by methylation status. A Cox proportional hazards model was fitted to control confounding factors, including age, white blood cell count, cytogenetic risk classification (favorable, intermediate, and poor risk), and TP53 mutations, as reported previously. Associations of methylation status with cytogenetic risk and somatic alterations were examined using the Wilcoxon and Kruskal-Wallis rank sum tests, respectively. Spearman rank correlation coefficient ( R) was used to evaluate correlations between methylation and expression. Results: Of the 200 patients, 109 (54.5%) were men, and median (interquartile range [IQR]) age was 57.5 (44.75-67) years. Median (IQR) methylations of promoter and body were 5.2% (4.8%-5.7%) and 55.6% (53.7%-57.9%), respectively. Body methylation was observed to correlate with gene expression ( R, -0.22; P = .005), but not promoter methylation. In Kaplan-Meier analysis, low methylation of body rather than promoter predicted prolonged OS (median, 27.4 vs 9.2 months; hazard ratio [HR], 0.43; 95% CI, 0.29-0.63; P &lt; .001). Notably, the OS improvement persisted with multivariable Cox model adopted (HR, 0.64; 95% CI, 0.42-0.98; P = .038). In addition, the body hypomethylation was strongly associated with early age, favorable cytogenetic risk, mutations in TP53, NPM1, and IDH1/ 2, as well as PML- RARA and MYH11- CBFB fusions (all P &lt; .05). Further analysis identified that cg08300570, cg09653641, cg10481072, and cg13590558 in the body were all prognostic for OS (all P &lt; .05). Intriguingly, all these CpGs resides in the enhancer. Conclusions: This is the first study to unravel clinical significance of CDK6 body methylation in AML, and it may serve as an independent prognostic marker. Given that azacitidine and decitabine are widely used, our findings may have implications for combination therapy of CDK4/6 inhibitors with hypomethylating agents in AML. Prospective studies are warranted.